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For a series of monosubstituted arylguanidines, 5-HT3 receptor affinity was found generally related to the electron withdrawing nature of the substituent at the aryl 3-position and the lipophilicity of the 4-position substituent. A broader examination of 35 arylguanidines and arylbiguanides revealed that affinity could be described by molecular polarizability, a Chi index term (8χP), and the sum of all (–Cl) E-State values (SsCl) in the molecule. [Copyright &y& Elsevier]

The present investigation examined two features of arylbiguanide and arylguanidine 5-HT3 ligands: conformation and partition coefficients. Several conformationally-constrained analogues of mCPBG (2) and mCPG (11; Ki=32 nM) were prepared and of these only 2-amino-5-chloro-3,4-dihydroquinazoline (14; Ki=34 nM) retained high affinity. The partition coefficient of compound 11 (LogPapp=−0.64) was less than that of its corresponding arylbiguanide 2 (LogPapp=−0.38). The quinazoline structure may represent a pharmacologically-active conformation of these agents, and the arylbiguanides were found more lipid soluble than their arylguanidine counterparts at physiological pH. [Copyright &y& Elsevier]